Recipients of solid organ transplants develop lymphoproliferative disorders of Epstein-Barr virus (EBV)-infected B cells. In addition, interleukin-6 (IL-6) promotes growth of EBV-infected B cells in vitro and in vivo. To study a potential role of IL-6 in the development of post-transplant lymphoproliferative disorders (PTLD), we have measured IL-6 levels in serum samples of 14 solid organ transplant recipients. Six of these patients who did not develop PTLD had normal IL-6 levels (5-15 U/ml) for 45 to 215 days post transplant. In contrast, 6 of 7 patients who developed PTLD had abnormally elevated serum IL-6 levels (85-1040 U/ml)at various timepoints post transplant (5-310 days). In all but one of these 7 cases, serum IL-6 levels were abnormally elevated before (3-45 days) PTLD was diagnosed. One patient with microscopic PTLD of the transplanted kidney had relatively normal serum IL-6 levels (18 U/ml). Finally, one of the 14 patients who died of sepsis 17 days post transplant had abnormally high IL-6 levels (50-103 U/ml) prior to death. Mean IL-6 levels in the culture supernatants of 5 single cell suspended PTLD lesions were greater than 1500 U/ml, while mean IL-6 levels in culture supernatants of peripheral blood of patients with acute infectious mononucleosis were less than 15 U/ml. Together, these findings demonstrate that, generally, IL-6 levels are abnormally elevated in sera of PTLD patients, and suggest that IL-6 may have a role in the pathogenesis of PTLD.